Inflammatory bowel disease (IBD), such as ulcerative colitis and Crohn""s disease, for example, can be a debilitating and progressive disease involving inflammation of the gastrointestinal tract affecting an estimated two million people in the United States. Symptoms include abdominal pain, cramping, diarrhea and rectal bleeding. IBD treatments have included anti-inflammatory drugs (such as, corticosteroids and sulfasalazine), immunosuppressive drugs (such as, 6-mercaptopurine, cyclosporine and azathioprine) and surgery (such as, colectomy). Podolsky, The New England Journal of Medicine, 325:928-937 (1991) and Podolsky, The New England Journal of Medicine, 325:1008-1016 (1991).
Some studies have suggested that the cell adhesion molecule, ICAM-1, mediates leukocyte recruitment to inflammatory sites through adhesion to leukocyte surface ligands, i.e. Mac-1, LFA-1 or xcex14xcex22 (Springer, Nature, 346:425-434 (1990)). In addition, vascular cell adhesion molecule-1 (VCAM-1), recognizing the xcex14xcex21 integrin (VLA-4), has been reported to play a role in in vivo leukocyte recruitment as well (Silber et al., J. Clin. Invest. 93:1554-1563 (1994)). It has been proposed that IBD can be treated by blocking the interaction of ICAM-1 with LFA-1 or Mac-1 or VCAM-1 with xcex14xcex21 (e.g., WO 93/15764). However, these therapeutic targets are likely involved in inflammatory processes in multiple organs, and a functional blockade would likely result in systemic immune dysfunction.
Mucosal addressin MAdCAM, a mucosal vascular adhesion molecule, is a 58-66K glycoprotein adhesion receptor for lymphocytes which is distinct from VCAM-1 and ICAM-1 (Briskin et al., Nature, 363:461-463 (1993)). In contrast to VCAM-1 and ICAM-1, MAdCAM is preferentially expressed in the gastrointestinal tract, binds the xcex14xcex27 integrin (also called LPAM-1 and CD49d/CDxe2x88x92) found on lymphocytes, and participates in the homing of these cells to mucosal sites, such as Peyer""s patches in the intestinal wall (Hamann et al., Journal of Immunology, 152:3282-3293 (1994)). The use of inhibitors to the binding of MAdCAM to the receptor, xcex14xcex27, in the treatment of diseases such as IBD has not been suggested.
The invention relates to the treatment of individuals suffering from a disease associated with leukocyte recruitment to the gastrointestinal tract as a result of binding of leukocytes to gut-associated endothelium expressing the molecule MAdCAM, comprising administering to the individual an effective amount of a compound, such as an antibody, which inhibits the binding of leukocytes to endothelial MAdCAM. The antibody is preferably monoclonal, chimeric and/or humanized or an antigen binding fragment thereof, and inhibits adhesion of leukocytes expressing an integrin containing the xcex27 chain (such as xcex14xcex27) to endothelium expressing MAdCAM. In one embodiment, the monoclonal antibody or antigen binding fragment thereof has the antigenic specificity of a monoclonal antibody selected from the group consisting of FIB 21, FIB 30, FIB 504 and ACT-1. Inflammatory bowel diseases, such as but not limited to ulcerative colitis, Crohn""s disease, Pouchitis, celiac disease, microscopic or collagenous colitis, and eosinophilic gastroenteritis can be treated according to the claimed method.